Novel Technologies in Plasma Fractionation. Dieter Fassnacht

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1 Novel Technologies in Plasma Fractionation Dieter Fassnacht

2 Agenda Grifols Overview Grifols Engineering Innovations in - Pooling - Fractionation - Filling Developing new technologies to provide innovative solutions is a core value to Grifols Grifols Therapeutics Plant in Clayton, North Carolina, USA 2

3 Grifols Overview Grifols is the world s third largest producer of plasma derived medicines. 13,900 employees worldwide committed to serving patients affected by life-threatening conditions. Hospital Division Manufactures standard parental solutions, medical devices and logistics platforms for hospitals Diagnostics Division - Supplies industry with clinical analysis and laboratory testing tools. Produces analyzers, reagents, instrumentation and products to collect, process and store blood Bioscience Division - Treatment of medical conditions using blood components. Plasma collection and testing, manufacturing, marketing and sales, R&D Bioscience manufacturing sites are located in Parets del Vallès, Spain; Clayton, North Carolina and Los Angeles. Recent Acquisitions 2011: Grifols acquires Talecris Biotherapeutics for $ 3.4 billion 2014: Grifols acquires Novartis Diagnostics Unit for $ 1.7 billion 3 Stock Information New York: GRFS Madrid: GRF.MC

Grifols Engineering Developing new technologies

a core value tor Grifols since founding of the

Inheriting this spirit Grifols Engineering was

solutions within the company but also to other

External Experience Engineering projects include

$fractionation industry, purification and fill$

4 Grifols Engineering Developing new technologies and expertise to provide innovative solutions is a core value tor Grifols since founding of the company. Inheriting this spirit Grifols Engineering was established in 2001 to provide engineering solutions within the company but also to other pharmaceutical clients. External Experience Engineering projects include consulting, process engineering, feasibility studies, conceptual and detail design, construction and start-up services Machinery projects include specialized equipment for the fractionation industry, purification and fill lines. Plasma Fractionation Technology 1 COLLECTION 2 TESTING 3 POOLING 4 FRACTIONATION 5 PURIFICATION 6 FILLING 4

Pooling Combination of up to 11,000 frozen donations into single batch Challenges of Pooling Thawing and combination process needs to be fast to minimize loses

handled in Class C Large amount of material handling (donations in, frozen product out, pallets and totes out, wastes out) 1 L Plasma Bottle 5 Traditional

5 Pooling Combination of up to 11,000 frozen donations into single batch Challenges of Pooling Thawing and combination process needs to be fast to minimize loses in product yield Difficulties in opening and emptying containers to remove frozen plasma Plasma containers are either bottles or bags Open product needs to be handled in Class C Large amount of material handling (donations in, frozen product out, pallets and totes out, wastes out) 1 L Plasma Bottle 5 Traditional Approach Labor intensive manual process with bio-burden and injury risks. Thawing and recovery rate of each individual donation is highly inconsistent 0.5 L Plasma Bag

Cutting station to open bottle Bottle lids are discarded into waste chute 6.

6 Automatic Bottle Opener Loading Side (Class D) 1. Manual Loading of Bottles 2. Skin-Thaw with Hot water 3. Rinse with AWFI 6 Unloading Side (Class C) 4. Air blow to dry bottles 5. Cutting station to open bottle Bottle lids are discarded into waste chute 6. Robot empties frozen plasma slugs into chute to vessel Detects failure to eject via weight change, then retry 7. Drip from empty bottles is collected for extra recovery 8. Empty bottles discarded into waste chute Loading side in Class D Unloading side in Class C (Level below contains Pooling vessels)

Plasma Bag Opener Method to skin-thaw is similar as for bottles Two parallel conveyers in single tunnel to increase throughput. Extended drying due to irregular bag shape Novel Plasma Bag Opener 1.

7 Plasma Bag Opener Method to skin-thaw is similar as for bottles Two parallel conveyers in single tunnel to increase throughput. Extended drying due to irregular bag shape Novel Plasma Bag Opener 1. Robot grabs bag and pulls it across stationary knife 2. Two rollers squeeze frozen plasma block out of plastic. 3. Camera system automatically detects unsuccessful discharge. Two parallel robots work independently to increase pooling rate 7

bottles and caps fall to ground floor Frozen plasma fall via chute to horizontal thaw vessels on mezzanine below Pallet lifts to

8 Semi-Continuous Pooling Minimization of residence time to increase cryoprecipitate yield Increase pooling rate to shorten process step Semi-continuous by starting product separation while still emptying plasma containers Vertical Facility Integration Empty bottles and caps fall to ground floor Frozen plasma fall via chute to horizontal thaw vessels on mezzanine below Pallet lifts to transport plasma from ground floor and return empty pallets and totes Plasma Freezer Plasma Lift Automatic Bottle Opener Pooling Vessel Waste 8

$fractions from the plasma.$ Proteins are then separated from the liquid via filtration or centrifugation Traditional Challenges in Fractionation Sub-freezing

Proteins are then separated from the liquid via filtration or centrifugation Traditional Challenges in Fractionation Sub-freezing

9 Fractionation Successive additions of ethanol and buffers and temperature changes as low as -7ºC precipitates certain protein fractions from the plasma. Proteins are then separated from the liquid via filtration or centrifugation Traditional Challenges in Fractionation Sub-freezing process requires -5ºC harsh work environment Open processing requires extensive clean-room areas Separation equipment (centrifuges or filter-presses) often requires manual cleaning Open handling of ethanol requires expensive electrical installations 9

Minimize Clean Room Space Move process equipment from

clean rooms Facilitate maintenance activities from

energy consumption Process Vessels Unique manway neck

10 Minimize Clean Room Space Move process equipment from clean room into technical space Improve cleanability of clean rooms Facilitate maintenance activities from non-clean room side Save construction cost and long term energy consumption Process Vessels Unique manway neck and inclined plane allow vessel installation in technical space 10

Centrifuges Clean room only contains rotating bowl and paste collection vessel.

11 Minimize Clean Room Space Process Vessels Move vessels entirely into technical space Closed additions Permanent piping for CIP Aseptic sampling from instrument belt. Centrifuges Clean room only contains rotating bowl and paste collection vessel. Motor, belt drive, lift for paste collection unit above clean room ceiling Processing support skid in technical space behind clean room wall. 11

standby, cleaning, equipment preparation Cool down to -7ºC takes about 2 hours and is initiated when required (e.g. harvest for filterpresses) Equipment innovations New centrifuge type does not require cold room.

12 12 Minimize Cold Production Space Eliminate or reduce cold processing space Provide better work environment Improve cleanability of clean rooms Save construction cost and long term energy consumption Dual temperature rooms Room is maintained at +5ºC for standby, cleaning, equipment preparation Cool down to -7ºC takes about 2 hours and is initiated when required (e.g. harvest for filterpresses) Equipment innovations New centrifuge type does not require cold room. Product is fully enclosed and cooled via jacketed vessel

13 Maximize Use of Natural Light Increase natural lighting Provide more pleasant work environment Increase of glass facilitates communication between areas 13

14 Highlights Process: Plasma Fractionation through IV-1 paste Separation Technology: Centrifugation Capacity: up to 6

14 North Fractionation Facility Key Figures Location: Clayton, NC, USA Size: 150,000 sq. ft. Project Cost: $ 343 million Construction Duration: 24 month FDA Licensure: November 2014 without pre-approval inspection! 14 Highlights Process: Plasma Fractionation through IV-1 paste Separation Technology: Centrifugation Capacity: up to 6 MML of plasma per year Batch size: 9,000 L (world s largest) Maximized closed processing and automation Minimized cold processing rooms and clean room space

15 Highlights Process: Fractionation from IV-4 to Albumin Separation Technology: Filtration Tied into NFF utilities,

15 North Fractionation Facility Expansion Key Figures Location: Clayton, NC, USA Size: 39,000 sq. ft. Project Cost: $ 28 million Construction Duration: 12 month FDA Licensure: November 2014 without pre-approval inspection! 15 Highlights Process: Fractionation from IV-4 to Albumin Separation Technology: Filtration Tied into NFF utilities, process support and gowning Optimal use of natural light Fast-track project executed in-house; engineering, project and construction management

16 Fractionament IV Key Figures Location: Parets del Valles, Spain Size: 1250 sq. m. footprint 3 stories Project Cost: 25 million Timeline Civil Works: Sep 2011 Jun 2012 Installation: May 2012 Jul 2013 Validation: Sept 2013 Jan 2014 EMA Licensure: May 2014 FDA Licensure: Dec Highlights Process: Plasma Fractionation through V paste Separation Technology: Centrifugation Capacity: up to 4 MML of plasma per year Batch size: 7,000 L Fast Track construction Minimized cold processing rooms and clean room space

$Ultrafiltration Skid The fractionation industry has special requirements related to viral inactivation /$

17 Purification Purification processes in Plasma Fractionation start with intermediate pastes and use typical purification unit operations used throughout the biotech: Ultrafiltration Chromatography CIP Ultrafiltration Skid The fractionation industry has special requirements related to viral inactivation / removal steps which include: Solvent Detergent treatment Thermal inactivation Nanofiltration Nanofiltration System 17

Nanofiltration system 120 m2 Ultrafiltration Skid 18 Main advantages: Better cost, schedule and scope control Design

18 Skid Design and Manufacturing Grifols as manufacturer of pharmaceuticals also designs and builds purifications skids in-house. Nanofiltration system 120 m2 Ultrafiltration Skid 18 Main advantages: Better cost, schedule and scope control Design experience remains within company Automation can be developed specific to manufacturing needs and software design experience greatly supports future troubleshooting Turn-over packages assembled for specific business needs to support for IOQ

19 Innovations in Filling Protective cap over stopper and vial guarantees sterility by providing labyrinth seal for microbes (principle of Pasteur flask). Cap is removed only seconds before actual fill and stoppering providing maximum protection. 19

Innovations in Filling Autoclave instead of depyrogenation oven provides decoupling of single equipment train to lessen impact of equipment failure allow staging of sterile vials before filling

20 Innovations in Filling Autoclave instead of depyrogenation oven provides decoupling of single equipment train to lessen impact of equipment failure allow staging of sterile vials before filling operation for fast product change-over Autoclaving fully assembled vials also provides easy sterilization of stopper Typical Filling Line Single continuous line Grifols Sterile Filling Line No separate stopper sterilization required Protective cap maximizes protection Decoupling of equipment Sterile staging for fast change-over 20

Two new liquid fill lines Fast-Track project engineered and constructed inhouse Viewing corridor

21 SFF Expansion Key Figures Location: Clayton, NC, USA Size: 23,000 sq. ft. Project Cost: $22 MM Construction Duration: 14 month FDA Licensure: Expected May 2016 Highlights Two new liquid fill lines Fast-Track project engineered and constructed inhouse Viewing corridor provides complete visibility to vial preparation and filling processes Novel design for Class A laminar flow recirculation 21

ENVIRONMENTAL PROGRAM

ENVIRONMENTAL PROGRAM 2017 2019 1 2 Specially protected biodiversity area, Clayton, North Carolina (Andrea Andersen) ENERGY INCREASE THE ENERGY EFFICIENCY OF EXISTING FACILITIES. REDUCE ELECTRICITY CONSUMPTION